GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity

Aikaterini Motso; Benjamin Pelcman; Anastasia Kalinovich; Nour Aldin Kahlous; Muhammad Hamza Bokhari; Nodi Dehvari; Carina Halleskog; Erik Waara; Jasper de Jong; Elizabeth Cheesman; Christine Kallenberg; Gopala Krishna Yakala; Praerona Murad; Erika Wetterdal; Pia Andersson; Sten van Beek; Anna Sandström; Diane Natacha Alleluia; Emanuela Talamonti; Sonia Youhanna; Pierre Sabatier; Claire Koenig; Sabine Willems; Aurino M. Kemas; Dana S. Hutchinson; Seungmin Ham; Lukas Grätz; Jan Voss; Jose G. Marchan-Alvarez; Martins Priede; Krista Jaunsleine; Jana Spura; Vadims Kovada; Linda Supe; Leigh A. Stoddart; Nicholas D. Holliday; Phillip T. Newton; Nicolas J. Pillon; Gunnar Schulte; Roger J. Summers; Ilga Mutule; Edgars Suna; Jesper V. Olsen; Peter Molenaar; Jens Carlsson; Volker M. Lauschke; Shane C. Wright; Tore Bengtsson

doi:10.1016/j.cell.2025.05.042

GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity

Aikaterini Motso
, Benjamin Pelcman
, Anastasia Kalinovich
, Nour Aldin Kahlous
, Muhammad Hamza Bokhari
, Nodi Dehvari
, Carina Halleskog
, Erik Waara
, Jasper de Jong
, Elizabeth Cheesman
, Christine Kallenberg
, Gopala Krishna Yakala
, Praerona Murad
, Erika Wetterdal
, Pia Andersson
, Sten van Beek
, Anna Sandström
, Diane Natacha Alleluia
, Emanuela Talamonti
, Sonia Youhanna

Pierre Sabatier, Claire Koenig, Sabine Willems, Aurino M. Kemas, Dana S. Hutchinson, Seungmin Ham, Lukas Grätz, Jan Voss, Jose G. Marchan-Alvarez, Martins Priede, Krista Jaunsleine, Jana Spura, Vadims Kovada, Linda Supe, Leigh A. Stoddart, Nicholas D. Holliday, Phillip T. Newton, Nicolas J. Pillon, Gunnar Schulte, Roger J. Summers, Ilga Mutule, Edgars Suna, Jesper V. Olsen, Peter Molenaar, Jens Carlsson, Volker M. Lauschke^*, Shane C. Wright^*, Tore Bengtsson^*

^*Corresponding author for this work

Atrogi AB
Stockholm University
Karolinska Institutet
Uppsala University
University of Queensland
Queensland University of Technology
University of Copenhagen
Monash University
Latvian Institute of Organic Synthesis
Excellerate Biosciences Ltd
University of Nottingham
Robert Bosch Foundation
University of Tübingen

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

Abstract

Biased agonism of G protein-coupled receptors (GPCRs) offers potential for safer medications. Current efforts have explored the balance between G proteins and β-arrestin; however, other transducers like GPCR kinases (GRKs) remain understudied. GRK2 is essential for β₂ adrenergic receptor (β₂AR)-mediated glucose uptake, but β₂AR agonists are considered poor clinical candidates for glycemic management due to G_s/cyclic AMP (cAMP)-induced cardiac side effects and β-arrestin-dependent desensitization. Using ligand-based virtual screening and chemical evolution, we developed pathway-selective agonists of β₂AR that prefer GRK coupling. These compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared with standard β₂-receptor agonists and incretin mimetics, respectively. Furthermore, the lead candidate showed favorable pharmacokinetics and was well tolerated in a placebo-controlled clinical trial. GRK-biased β₂AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.

Original language	English
Pages (from-to)	5142-5156.e23
Journal	Cell
Volume	188
Issue number	19
DOIs	https://doi.org/10.1016/j.cell.2025.05.042
Publication status	Published - 18 Sept 2025
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

BRET
GLP-1
GPCR
GRK
beta-2 agonists
biased agonism
diabetes
metabolism
obesity
skeletal muscle

Access to Document

10.1016/j.cell.2025.05.042

Cite this

Motso, A., Pelcman, B., Kalinovich, A., Kahlous, N. A., Bokhari, M. H., Dehvari, N., Halleskog, C., Waara, E., de Jong, J., Cheesman, E., Kallenberg, C., Yakala, G. K., Murad, P., Wetterdal, E., Andersson, P., van Beek, S., Sandström, A., Alleluia, D. N., Talamonti, E., ... Bengtsson, T. (2025). GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity. Cell, 188(19), 5142-5156.e23. https://doi.org/10.1016/j.cell.2025.05.042

@article{a8688228cd29447db2f0e9fc89eb912e,

title = "GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity",

abstract = "Biased agonism of G protein-coupled receptors (GPCRs) offers potential for safer medications. Current efforts have explored the balance between G proteins and β-arrestin; however, other transducers like GPCR kinases (GRKs) remain understudied. GRK2 is essential for β2 adrenergic receptor (β2AR)-mediated glucose uptake, but β2AR agonists are considered poor clinical candidates for glycemic management due to Gs/cyclic AMP (cAMP)-induced cardiac side effects and β-arrestin-dependent desensitization. Using ligand-based virtual screening and chemical evolution, we developed pathway-selective agonists of β2AR that prefer GRK coupling. These compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared with standard β2-receptor agonists and incretin mimetics, respectively. Furthermore, the lead candidate showed favorable pharmacokinetics and was well tolerated in a placebo-controlled clinical trial. GRK-biased β2AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.",

keywords = "BRET, GLP-1, GPCR, GRK, beta-2 agonists, biased agonism, diabetes, metabolism, obesity, skeletal muscle",

author = "Aikaterini Motso and Benjamin Pelcman and Anastasia Kalinovich and Kahlous, \{Nour Aldin\} and Bokhari, \{Muhammad Hamza\} and Nodi Dehvari and Carina Halleskog and Erik Waara and \{de Jong\}, Jasper and Elizabeth Cheesman and Christine Kallenberg and Yakala, \{Gopala Krishna\} and Praerona Murad and Erika Wetterdal and Pia Andersson and \{van Beek\}, Sten and Anna Sandstr{\"o}m and Alleluia, \{Diane Natacha\} and Emanuela Talamonti and Sonia Youhanna and Pierre Sabatier and Claire Koenig and Sabine Willems and Kemas, \{Aurino M.\} and Hutchinson, \{Dana S.\} and Seungmin Ham and Lukas Gr{\"a}tz and Jan Voss and Marchan-Alvarez, \{Jose G.\} and Martins Priede and Krista Jaunsleine and Jana Spura and Vadims Kovada and Linda Supe and Stoddart, \{Leigh A.\} and Holliday, \{Nicholas D.\} and Newton, \{Phillip T.\} and Pillon, \{Nicolas J.\} and Gunnar Schulte and Summers, \{Roger J.\} and Ilga Mutule and Edgars Suna and Olsen, \{Jesper V.\} and Peter Molenaar and Jens Carlsson and Lauschke, \{Volker M.\} and Wright, \{Shane C.\} and Tore Bengtsson",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = sep,

day = "18",

doi = "10.1016/j.cell.2025.05.042",

language = "English",

volume = "188",

pages = "5142--5156.e23",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "19",

}

Motso, A, Pelcman, B, Kalinovich, A, Kahlous, NA, Bokhari, MH, Dehvari, N, Halleskog, C, Waara, E, de Jong, J, Cheesman, E, Kallenberg, C, Yakala, GK, Murad, P, Wetterdal, E, Andersson, P, van Beek, S, Sandström, A, Alleluia, DN, Talamonti, E, Youhanna, S, Sabatier, P, Koenig, C, Willems, S, Kemas, AM, Hutchinson, DS, Ham, S, Grätz, L, Voss, J, Marchan-Alvarez, JG, Priede, M, Jaunsleine, K, Spura, J, Kovada, V, Supe, L, Stoddart, LA, Holliday, ND, Newton, PT, Pillon, NJ, Schulte, G, Summers, RJ, Mutule, I, Suna, E, Olsen, JV, Molenaar, P, Carlsson, J, Lauschke, VM, Wright, SC & Bengtsson, T 2025, 'GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity', Cell, vol. 188, no. 19, pp. 5142-5156.e23. https://doi.org/10.1016/j.cell.2025.05.042

TY - JOUR

T1 - GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity

AU - Motso, Aikaterini

AU - Pelcman, Benjamin

AU - Kalinovich, Anastasia

AU - Kahlous, Nour Aldin

AU - Bokhari, Muhammad Hamza

AU - Dehvari, Nodi

AU - Halleskog, Carina

AU - Waara, Erik

AU - de Jong, Jasper

AU - Cheesman, Elizabeth

AU - Kallenberg, Christine

AU - Yakala, Gopala Krishna

AU - Murad, Praerona

AU - Wetterdal, Erika

AU - Andersson, Pia

AU - van Beek, Sten

AU - Sandström, Anna

AU - Alleluia, Diane Natacha

AU - Talamonti, Emanuela

AU - Youhanna, Sonia

AU - Sabatier, Pierre

AU - Koenig, Claire

AU - Willems, Sabine

AU - Kemas, Aurino M.

AU - Hutchinson, Dana S.

AU - Ham, Seungmin

AU - Grätz, Lukas

AU - Voss, Jan

AU - Marchan-Alvarez, Jose G.

AU - Priede, Martins

AU - Jaunsleine, Krista

AU - Spura, Jana

AU - Kovada, Vadims

AU - Supe, Linda

AU - Stoddart, Leigh A.

AU - Holliday, Nicholas D.

AU - Newton, Phillip T.

AU - Pillon, Nicolas J.

AU - Schulte, Gunnar

AU - Summers, Roger J.

AU - Mutule, Ilga

AU - Suna, Edgars

AU - Olsen, Jesper V.

AU - Molenaar, Peter

AU - Carlsson, Jens

AU - Lauschke, Volker M.

AU - Wright, Shane C.

AU - Bengtsson, Tore

PY - 2025/9/18

Y1 - 2025/9/18

N2 - Biased agonism of G protein-coupled receptors (GPCRs) offers potential for safer medications. Current efforts have explored the balance between G proteins and β-arrestin; however, other transducers like GPCR kinases (GRKs) remain understudied. GRK2 is essential for β2 adrenergic receptor (β2AR)-mediated glucose uptake, but β2AR agonists are considered poor clinical candidates for glycemic management due to Gs/cyclic AMP (cAMP)-induced cardiac side effects and β-arrestin-dependent desensitization. Using ligand-based virtual screening and chemical evolution, we developed pathway-selective agonists of β2AR that prefer GRK coupling. These compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared with standard β2-receptor agonists and incretin mimetics, respectively. Furthermore, the lead candidate showed favorable pharmacokinetics and was well tolerated in a placebo-controlled clinical trial. GRK-biased β2AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.

AB - Biased agonism of G protein-coupled receptors (GPCRs) offers potential for safer medications. Current efforts have explored the balance between G proteins and β-arrestin; however, other transducers like GPCR kinases (GRKs) remain understudied. GRK2 is essential for β2 adrenergic receptor (β2AR)-mediated glucose uptake, but β2AR agonists are considered poor clinical candidates for glycemic management due to Gs/cyclic AMP (cAMP)-induced cardiac side effects and β-arrestin-dependent desensitization. Using ligand-based virtual screening and chemical evolution, we developed pathway-selective agonists of β2AR that prefer GRK coupling. These compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared with standard β2-receptor agonists and incretin mimetics, respectively. Furthermore, the lead candidate showed favorable pharmacokinetics and was well tolerated in a placebo-controlled clinical trial. GRK-biased β2AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.

KW - BRET

KW - GLP-1

KW - GPCR

KW - GRK

KW - beta-2 agonists

KW - biased agonism

KW - diabetes

KW - metabolism

KW - obesity

KW - skeletal muscle

UR - https://www.scopus.com/pages/publications/105008784450

U2 - 10.1016/j.cell.2025.05.042

DO - 10.1016/j.cell.2025.05.042

M3 - Article

C2 - 40555230

AN - SCOPUS:105008784450

SN - 0092-8674

VL - 188

SP - 5142-5156.e23

JO - Cell

JF - Cell

IS - 19

ER -

GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity

Abstract

UN SDGs

Keywords

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